BIPHASIC DOSE-RESPONSE RELATIONSHIPS 61these mechanisms may result in remarkable progression of tissue injury in
an unabated fashion. A greater understanding of the biochemical mecha
nisms underlying hormesis would not only lead to a better understanding of
the mechanistic basis for the “threshold” concept, but it is also likely to
provide us with a rational basis for the assessment of risk at low-level
exposures to chemical and physical agents.
This chapter focuses on the hepatotoxic effects of low-level exposure to
halomethane solvents. The discovery of tissue-healing mechanisms stimu
lated as a hormetic response to limited liver injury was made only through
work with exposures of experimental animals to low levels of halomethanes.
The most compelling reason for investigating the toxicology of low levels of
halomethanes was provided by the observation that at individually nontoxic
doses, the combination of exposure to a chlorinated pesticide chlordecone
(Kepone) and a halomethane such as CC1 4 causes an unprecedented level of
toxic injury.2 In order that the experimental evidence for the existence of
inducible hormetic mechanisms in the form of tissue repair directed to
overcoming tissue injury can be discussed in the context of its discovery, the
toxicology of halomethanes, and the interactive toxicity of halomethanes in
combination with exposure to other chemicals, will be reviewed.
MECHANISM OF HALOMETHANE HEPATOTOXICITYCarbon Tetrachloride
The mechanism of CCl4-induced hepatotoxicity has been extensively
studied.12 23 Since the mechanism underlying the toxicology of CC1 4 is cen
tral to the consideration of how its toxicity might affect the liver tissue and
how this might be modified by other chemicals, it is worthwhile to outline
the prevailing concepts concerning the hepatotoxicity of CC14.
Several reviews have appeared on this topic.1216 The leading theory for
the mechanism of cellular damage caused by CC1 4 is that the compound is
bioactivated by cytochrome P-450 mediated reactions to CC1 3 free-
radical,12-151723 which is further converted to a peroxy radical, CC1 30 2.15,20
There is evidence for covalent binding of CC1 4 upon bioactivation.12-23 The
CC1 302 radical is also thought to decompose to phosgene and electrophilic
Cl-, which can react with other macromolecules.24 The free radicals CC1 3
and CC1 302 readily react with polyunsaturated fatty acids of the endoplas
mic reticulum and other hepatocellular membranes to initiate the formation
of organic lipid peroxides. In the presence of cellular 0 2, these organic
peroxy radicals in turn can react with other polyunsaturated fatty acids to
perpetuate a series of self-propagating chain reactions, a process commonly
referred to as “propagation of lipid peroxidation.” 12 The bioactivation of
CC1 4 and initiation of the self-propagating lipid peroxidation, working in
tandem, destroy the cellular membranes, leading to cell death. The principal